What is the role of regional chemotherapy in BSTTs?

Introduction

The major goal of treating sarcoma in the extremities is to achieve long-term control and to preserve function wherever possible. This is particularly important as amputation does not improve survival rates in patients with large (>5cm) deep-seated high grade sarcomas. Limb salvage offers significant benefit to the patient and community in terms of function, work productivity, rehabilitation and overall cost.

Surgical therapy remains problematic for patients with large primary tumours and those with bulky recurrent disease. Local recurrence rates are directly related to the type and extent of surgery and/or radiotherapy undertaken and range between 10-80%. Criteria of irresectability include multifocal primary tumours, multiply recurrent limb tumours, fixation to or invasion into neurovascular bundles and/or bone and tumour recurrences in previously irradiated areas.

Isolated limb perfusion (ILP) has been used in patients with extremity STS for > 40 years. In the majority of patients, this approach has been used as a limb-sparing alternative when amputation was considered the only treatment option.

The proposed advantages of ILP include: isolation from the systemic circulation which permits administration of high dose cytotoxic chemotherapy; tumouricial effects of hyperthermia and potentially down-staging of STS which may permit subsequent limb sparing surgery.

Several contentious questions persist in relation to the appropriate drug or drug combinations, the use of tumour necrosis factor – alfa (TNFα), the use of ILP in the pre-operative setting and the use of isolated limb infusion (ILI) as an alternative to isolated limb perfusion (ILP).[1]

Several large studies from European centres suggest that ILP with combination melphalan and TNFα should be considered as first line therapy for patients with large high grade primary extremity STS. However, it is not possible to subject this treatment to a true randomised control trial as STS is a relatively rare condition.[2]

Australian experience with ILP is limited to only a few specialised centres. TNFα is not currently available in Australia due to licencing issues.

Role of ILP in limb salvage, prior to consideration of amputation

No randomised controlled trial or other comparative study was available comparing ILP with other treatment options (e.g. pre-operative or amputation) for locally unresectable soft tissue sarcoma (STS).

The best available evidence (i.e. largest series) comes from a retrospective, multicentre study involving eight European centres,[3] each of which used a standardised protocol with melphalan and TNFα in 186 patients.

These findings are consistent with other series from different institutions, reporting overall response rates for ILP in unresectable STS varying between 77% to 94%, with acceptable regional and systemic toxicity.[4][5]

ILP is also warranted for patients with metastatic disease, and advanced local extremity disease, as an alternative to amputation.[6]

Efficacy of ILP with melphalan alone vs melphalan + TNFα

ILP is provided in a limited number of Australian centres. Some centres provide a simplified version of ILP called isolated limb infusion (ILI). ILI utilises a low-pressure hypoxic circuit rather than an oxygenated pressurised perfusion circuit. One Australian study reports a series of 21 patients with extremity STS undergoing ILI. The overall response rate was 90% and the overall limb salvage rate 76%.[7] Systemic leakage monitoring is not performed with ILI, making it unsuitable for use with TNFα.

Melphalan is the standard cytotoxic aged used in ILP. Other cytotoxic agents such as cisplatin and doxorubicin have been used and report similar efficacy. More recently TNFα has been used in combination with melphalan to increase efficacy rates. TNFα has indirect antitumour effects on the tumour vascular bed.[1] Although most single centre series report higher response rates with melphalan + TNFα for extremity sarcoma, there are no randomised studies comparing with melphalan. The toxicity profile of TNFα mandates systemic leakage monitoring. TNFα is not available in Australia for ILP.

Evidence summary and recommendations

Evidence summary

Level

References

Isolated limb perfusion is an effective limb-sparing option for patients with unresectable extremity soft tissue sarcoma. In selected patients it may provide an alternative to amputation; as either a 'downstaging' strategy for otherwise unresectable disease, or as a palliative strategy.